ABSTRACT The olfactory epithelium is one of the few sites where environmental pathogens can gain direct access to the brain. Olfactory sensory neurons in the olfactory epithelium have direct contact with the outside and their axons extend through the cribriform plate into the olfactory bulb. Despite its strategic location, little is known about the protective mechanisms in place to prevent viral infection and entry into the brain. Viruses frequently infect the respiratory epithelium, and the olfactory epithelium is a part of the upper respiratory tract that is exposed to viral insult. Several neurotropic viruses have been found to be able to infect olfactory sensory neurons and reach into the brain via the olfactory nerve under experimental settings. Despite the available ?highway?, viral entry into the brain via the nasal route is rarely reported clinically. In our preliminary studies, we detected robust early innate responses that are unique to the olfactory epithelium. We hypothesize that the olfactory epithelium possesses unique protective mechanisms against viral infection and replication in olfactory sensory neurons. To test the hypothesis, we will investigate the role of sustentacular cells which form the protective apical surface of the olfactory epithelium; we will subsequently determine host responses within the olfactory sensory neurons. Viral induced responses will be systematically studied by gene expression profiling and cell type specific responses will be determined by in situ hybridization. Data obtained from this study will provide a systematic view of the molecular players involved in nasal innate immunity and allow further mechanistic study to determine key checkpoints and regulatory steps.